Comparative study of conventional urothelial carcinoma, squamous differentiation carcinoma and pure squamous carcinoma in patients with invasive bladder tumors.

PURPOSE
Treatment results evaluation (radical cystectomy and adjuvant chemo/radiotherapy) in patients with urothelial carcinoma, squamous differentiation carcinoma and pure squamous bladder carcinoma.


MATERIAL AND METHODS
The study included 361 patients with invasive bladder carcinoma treated between 1990-2013. Histology showed 296 cases of urothelial carcinoma (82% - group A), 52 cases of urothelial divergent differentiation (squamous and urothelial carcinoma 14.4% - group B) and 13 cases of squamous cell carcinoma (3.6% - group C). All patients benefited from radical cystectomy. Adjuvant chemotherapy was undergone in 68 patients.


RESULTS
Group A - urothelial carcinoma - had a 44% rate of patients alive with a mean survival period of 73 months. About 56% of the patients died, the mean survival period being 4 years. Group B - urothelial carcinoma with squamous differentiation - had a mean survival period of 36 months (between 1-156 months). 17 patients (33%) are alive at 50 months postoperatively. Group C - squamous carcinoma - had a mean survival period of 9.4 months.


DISCUSSIONS
Locally advanced disease was diagnosed in 50% of the patients in group A, while in group B the rate was 84.6% and 70% in group C, respectively.


CONCLUSIONS
Squamous pattern detected in the histopathological specimen represents a negative prognostic factor. It seems that the squamous component influences the outcome of the disease due to its biological characteristics in the evolution of squamous carcinoma, with advanced local stage disease at diagnosis - late onset of symptoms and lack of response to adjuvant treatment.

Squamous cell carcinoma is a relatively rare disease, responsible for 1.4 -4.5% of all newly diagnosed bladder cancers in USA and Western Europe, mostly in the 7 th decade of life. Male female ratio found in literature is 1.25:1/1.8:1.
By definition, squamous cell bladder carcinoma does not include urothelial features. The main histological characteristic is the presence of keratin forming cells that have a pearly aspect and intercellular bridges (Qihui).
It is well known that each histological variant has a different biology, subsequently possessing an unique capacity of recurrence, metastasization and treatment response (P Black Urologic Oncology 2009). Therefore, these features must guide, influence and change the standard treatment protocol.

Material a
The bladder carc Histology sh cases of ur and urothelia carcinoma (T
Taking into consideration the etiology, squamous bladder carcinoma is divided into bilharzial type, commonly found in North Africa and nonbilharzial type, caused by chronic urinary infections, bladder stones, etc. [24], Messing reports in a study on a cohort of 1422 patients with nonbilharzial SCC diagnosed between 1988-2003 from SEER database, a mortality rate of 11% and 72%, respectively at 2 years for stage I and IV disease. After adjustment for age, gender, race and initial treatment, squamous cell carcinoma was associated with poor outcome when compared to urothelial cancer in patients that did not benefit from radical cystectomy in stage I and II and also for all patients (with or without cystectomy) in stage III and IV disease.
Comparative studies with urothelial carcinoma are causing controversy [1,8,11,19,21],. Craig analyzed 67 patients with nonurothelial carcinomas who represent 7% from a cohort of patients with invasive bladder cancer treated by radical cystectomy, showing that the 5-year survival rate for SCC was 55% vs 60% for transitional cell carcinoma.
Another recent study from MSK (Behfar 2012) which included 2031 patients with radical cystectomy, reported 78 cases of SCC and 67 cases of squamous differentiation. No major differences regarding survival are seen between the two groups.
Radiotherapy alone offers a 5-year survival rate of 12-31% [3,4,10,12]. Rundle [23], shows that the 1-year survival rate is 23.8%, while the 5-year survival rate is 1.9% in a study undergone between 1964 and 1978 on a cohort of 114 patients with SCC treated by radiotherapy.
Some studies argue in favor of neoadjuvant radiotherapy, but without any controlled studies [5,6].
In 1989, Swanson performed neoadjuvant radiotherapy (50Gy) in 25 patients who benefited from radical cystectomy . The results showed 25% [10] of patients with partial tumor regression and 24% of patients with total tumor regression -T0. No pelvic lymphadenectomy was performed in 20 patients. The 5year survival rate was 50%, with 43% for T3 and T4 stages.
In 2007, Kassouf [17], published a study consisting of 27 cases of SCC (1988SCC ( -2003 with a 2 year survival rate of 47.6% and a recurrence free survival rate of 32.8%. 8 patients received neodjuvant chemo +/radiotherapy. Due to disease progression, 5 patients did not fit for radical cystectomy. The other 3 patients showed disease regression in 2 cases after neodjuvant treatment and did not develop recurrences. 10 patients with radical cystectomy developed recurrences at a mean period of 5.1 months, 7 patients dying due to local recurrence (3 cases), distant metastasis (1 case) or both (3 cases). Median survival period, disease specific survival period and recurrence free survival period was estimated on Kaplan-Meier to be of 12.4 months, 12.4 months and 8.3 months respectively.
Squamous cell bladder carcinoma seems to have no response at chemotherapy [24,27]. Despite this fact, Glasky [7], published a study with complete response at administration of isophosphamide, paclitaxel and cisplatin in 2 out of 8 patients.
Data from literature reveals a low incidence of metastatic disease in SCC -8% [26]. Jones confirms such facts in a study on 51 patients with SCC showing that death event occurred by failure of local disease control rather than by distant metastasis.
In contrast to that, urothelial carcinoma tends to have local recurrences in 50% of the cases, while 50% associate distant metastasis with local recurrence [15]. Therefore, the need for a better pelvic control with negative surgical margins in the cystectomy specimen arises [26].
In our study, the response to adjuvant treatment must be correlated with the locally advanced disease at diagnosis (65% in urothelial carcinoma), tumor grading (78% -G3 and G4) and R2 disease (7 patients).
The squamous differentiation group recorded 75% of patients [9] with locally advanced disease, 91% having G3, while the SCC group recorded 60% of patients with locally advanced disease.
The most aggressive tumors tend to be the SCC. Better results regarding survival are observed in patients who receive adjuvant treatment compared to cystectomy alone (17.2 months vs 6 months).

Conclusions
Standard treatment for nonbilharzian SCC is radical cystectomy, offering local control for the disease. A feature of SCC seems to be advanced local disease -70% of patients. Therefore, death occurs more frequently by local recurrence rather than by distant metastasis. Neoadjuvant radiotherapy can be taken into consideration, as SCC is radiosensitive. Though data suggest that chemotherapy has no indication in SCC, in our study higher survival periods were achieved in the chemotherapy group.
Concerning the aggressiveness of these pathologies we can conclude that squamous carcinoma is the most aggressive, followed by squamous differentiation carcinoma with a median survival period of 33 months